Funded Projects

Opioid Use Disorder (OUD) prevalence has reached unprecedented levels among adolescents and emerging adults. Recovery Support Services (RSS) for persons with SUDs typically focus on the individual client after acute care. But for youth, developmental theory underscores the primacy of family-level risk and protective factors, and family-based interventions have the strongest empirical support. Yet there is a lack of research, clinical resources, and generalizable metrics focused on family-based RSS for youth with OUD. This study will establish a sustainable research network to develop and evaluate innovative family-based RSS across the youth OUD services cascade. The overall goal is to conduct research to strategies to promote family integration in youth OUD services, increase service engagement, and build supportive family environments for youth recovery. The specific goals focus on 1) innovations in family RSS interventions and metrics to assist youth OUD providers with integrating families in OUD services and, 2) innovations in measurement of direct-to-family RSS for families of youth with OUD. If successful, this study will systematically build a research and technical assistance infrastructure designed to develop and evaluate innovative family-based RSS for youth with OUD that span all phases of the services cascade: screening and referral, treatment initiation, treatment delivery, and continuing care.

An International Cooperative Biodiversity Group with an interdisciplinary leadership team of physicians, pharmacologists, evolutionary biologists, and chemists will discover and develop therapeutic agents produced by Brazilian symbiotic bacteria. The team will target three therapeutic areas: 1) infectious fungal pathogens, 2) Chagas disease and leishmaniasis, and 3) cancers of the blood. All three areas represent major threats to human health that need to be addressed with new therapeutic agents. Internationally, invasive fungal diseases kill more people than malaria or TB, while Chagas disease imposes a special burden on Brazil, killing as many Brazilians as TB. Leishmaniasis has now passed Chagas disease in the Brazilian population. Despite major improvements in cancer chemotherapy, cancer is projected to result in 8 million deaths internationally this year (13% of all deaths, WHO) and an estimated 13 million per year by 2030.

The Philippine Mollusk Symbiont International Cooperative Biodiversity Group harnesses the vast biodiversity of the Philippines to discover new drugs to treat bacterial infections, parasitic infections, pain, and other neurological conditions and cancer, all of which are serious health problems in both the Philippines and the United States. The Republic of the Philippines represents a unique nexus of exceptional biodiversity, dense human population with pressing societal needs, consequent urgent need for conservation, and government commitment to education and technology to harness national human and natural resources for a sustainable future. Mollusks are one of the most diverse groups of marine animals, and their associated bacteria represent an unexplored trove of chemical diversity. Researchers will use an increasing understanding of the interactions between mollusk symbionts and their hosts to discover the most novel and useful molecules. The project will document and describe Philippine mollusk biodiversity and support training and infrastructure that provide the foundation for conservation of Philippine biodiversity.

This project will build overdose models for fentanyl, methadone, codeine, and morphine in a multi-organ system and evaluate the acute and repeat dose, or chronic effects, of overdose treatments as well as off-target toxicity. Researchers developed a system using human cells in a pumpless multi-organ platform that allows continuous recirculation of a blood surrogate for up to 28 days. They will develop two overdose models for male and female phenotypes based on pre-B?tzinger Complex neurons and will integrate functional immune components that enable organ-specific or systemic monocyte actuation. Models for cardiomyopathy and infection will be utilized. Researchers will establish a pharmacokinetic/pharmacodynamic model of overdose and treatment to enable prediction for a range of variables. We will use a serum-free medium with microelectrode arrays and cantilever systems integrated on chip that allow noninvasive electronic and mechanical readouts of organ function.

Researchers will develop multi-organ, microphysiological systems (MPSs) based on human induced pluripotent stem cell-derived midbrain-fated dopamine (DA)/gamma-aminobutyric acid neurons on a three-dimensional platform that incorporates microglia, blood–brain barrier (BBB), and liver metabolism. RNA sequencing and metabolomics analyses will complement the primary DA release measure to identify novel mechanisms contributing to chronic opioid-induced plasticity in DA responsiveness. The chronic pain-relevant aspect of the model will be realized by examination of aversive kappa-mediated opioid effects on DA transmission in addition to commonly abused mu opioid receptor agonists, and by incorporation of inflammatory-mediating microglia. Incorporation of BBB and liver metabolism modules into the microphysiologic system platform will permit screening of drugs. Throughput will be increased by integration of online sensors for online detection of DA and other analytes. Researchers will use a curated set of 100 chemical genomics probes.

Hesperos uses microphysiological systems in combination with functional readouts to establish systems capable of analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing, with initial emphasis on predictive toxicity. The team constructed physiological systems that represent cardiac, muscle and liver function, and demonstrated a multi-organ functional cardiac/liver module for toxicity studies as well as metabolic activity evaluations. In addition, the team demonstrated multi-organ toxicity in a 4-organ system composed of neuronal, cardiac, liver and muscle components. While much is known about the cells and neural circuitry regulating pain modulation there is limited knowledge regarding the precise mechanism by which peripheral and spinal level antinociceptive drugs function, and no available human-based model reproducing this part of the pain pathway. The ascending pain modulatory pathways provide a well characterized neural architecture for investigating pain regulatory physiology. In this project, the research team propose a human-on-a-chip neuron tri-culture system composed of nociceptive neurons, GABAergic interneurons and glutamatergic dorsal projection neurons (DPN) integrated with a MEMS construct. Using this model, investigators will interrogate pain signaling physiology at three levels, 1) at the site of origin by targeting nociceptive neurons with pain modulating compounds including noxious stimuli and inflammatory mediators, 2) at the inhibitory GABAergic interneuron, and 3) at the ascending spinal level by targeting glutamatergic DPNs. These circuits will be integrated utilizing expertise in patterning neurons as well as integration with BioMEMs devices. This system provides scientists with a better understanding of ascending pain pathway physiology and enable clinicians to consider alternative indications for treating pain at peripheral and spinal levels. 

Chronic pain results in long-term changes throughout the central nervous system. These include abnormal structure and function of the frontal cortex region of the brain, which relays pain messages and also the common pain-related conditions depression, anxiety, and cognitive impairment. Peripheral nerve injury results in widespread and long-lasting changes to DNA in the frontal cortex. DNA methylation, in which chemical tags are attached to DNA, is one way the body controls the activity of genes over time. This control occurs via proteins that recognize tagged DNA, and some of these proteins do not work properly in the frontal cortex many months after nerve injury. These changes occur after nerve injury and are linked to mechanical sensitivity. This project will determine this DNA-binding protein is a good target for finding new medications for chronic pain. 

The clinical utility of opioids for pain treatment is limited by its risk for developing opioid usage disorders (OUD). These untoward effects impose a severe burden on society and present difficult therapeutic challenges for clinicians. We propose to extend our cerebral organoid MPS to facilitate the investigation of neuronal response to opioids and identify cellular and molecular signatures in patients vulnerable to OUD. We have assembled a team with complementary expertise in clinical characterization of OUD, cerebral organoid MPS modeling, single cell RNA-seq technology, and functional characterization of neurons in a mesolimbic reward system to test the hypothesis that midbrain MPS is a clinically relevant pre-clinical model for study of opioid usage disorder.

This project will develop PIDA, which will allow researchers to measure the activity of pain-sensitive human neurons in response to pain stimuli and potential pain treatments. The tool will use automated digital microscopes in the absence or presence of a potential pain medication. Since this tool contains human neurons, it may be more effective at predicting the efficacy of potential pain drugs in human patients than the animal models that are currently used.

Poor medication-assisted treatment (MAT) retention disproportionately affects low-income racial/ethnic minority individuals with opioid use disorder (OUD) and increases risk for relapse; therefore, evidence-based interventions are needed to improve MAT retention. Peer recovery coaches (PRCs), trained individuals with experiences with substance use disorder, may be uniquely suited to address common MAT retention barriers among underserved populations, including stigma, challenges navigating services, housing instability, and other structural and psychosocial factors. Preliminary work by the research team suggests that behavioral activation (BA) by PRCs may be a feasible, scalable reinforcement-based approach for improving MAT retention for low-income minority OUD individuals. The study builds upon the research team’s formative work to adapt and evaluate the effectiveness and implementation of a PRC-delivered BA intervention (Peer Activate) to improve MAT retention for low-income, minority individuals with OUD.